Jurima-Romet M, Huang H S
Toxicology Section, Health and Welfare Canada, Tunney's Pasture, Ottawa.
Biochem Pharmacol. 1993 Dec 14;46(12):2163-70. doi: 10.1016/0006-2952(93)90605-v.
Captopril and enalapril, angiotensin-converting enzyme inhibitors (ACEIs), have been associated with idiosyncratic hepatotoxicity. Such drug reactions may be caused by the formation of reactive metabolites by cytochrome P450 isozymes, which can then cause direct or immune-mediated toxicity. Previously, we have demonstrated that enalapril cytotoxicity in primary cultures of rat hepatocytes was due, at least in part, to cytochrome P450-dependent metabolism, and that glutathione was involved in the detoxification process. In the present study, we extended our investigations into mechanisms of cytotoxicity, using rat hepatocyte cultures, to captopril and three recently marketed ACEIs: fosinopril, lisinopril and quinapril. After 24 hr of exposure to lisinopril or enalaprilat (the deesterified metabolite of enalapril), hepatocytes did not show any evidence of cytotoxicity, measured by lactate dehydrogenase leakage, even at 10 mM drug concentrations. The other ACEIs were toxic to the liver cells, with the rank order of toxicity as quinapril (LC50 = 0.28 mM) > fosinopril (LC50 = 0.4 mM) > enalapril (LC50 = 2.0 mM) > captopril (LC50 = 20 mM). In vivo pretreatment of rats with pregnenolone-16 alpha-carbonitrile to induce isozymes of the P450 3A subfamily significantly enhanced the cytotoxicities of quinapril, fosinopril and enalapril but did not affect captopril cytotoxicity. Pretreatment with P450 inducers selective for other isozyme subfamilies (ethanol, beta-naphthoflavone and phenobarbital) did not alter the in vitro toxicity of any of the ACEIs. Co-incubation with SKF525-A (15 microM) or troleandomycin (0.1 mM) reduced the hepatocidal toxicities of quinapril, fosinopril and enalapril. Preincubation with buthionine sulfoximine (2 mM) enhanced the cytotoxicities of quinapril, fosinopril, enalapril and captopril. The results of this study indicate that like enalapril, quinapril and fosinopril can also undergo P450 3A-dependent bioactivation and require maintenance of glutathione status for detoxification, and that captopril causes cytotoxicity independent of cytochrome P450 metabolism.
血管紧张素转换酶抑制剂（ACEIs）卡托普利和依那普利与特异质性肝毒性有关。此类药物反应可能是由细胞色素P450同工酶形成反应性代谢产物所致，这些代谢产物随后可引起直接毒性或免疫介导的毒性。此前，我们已证明依那普利在大鼠肝细胞原代培养物中的细胞毒性至少部分归因于细胞色素P450依赖性代谢，且谷胱甘肽参与解毒过程。在本研究中，我们利用大鼠肝细胞培养物，将对细胞毒性机制的研究扩展至卡托普利以及三种最近上市的ACEIs：福辛普利、赖诺普利和喹那普利。在暴露于赖诺普利或依那普利拉（依那普利的去酯代谢产物）24小时后，即使在10 mM药物浓度下，通过乳酸脱氢酶泄漏测定，肝细胞也未显示出任何细胞毒性迹象。其他ACEIs对肝细胞有毒性，毒性顺序为喹那普利（LC50 = 0.28 mM）>福辛普利（LC50 = 0.4 mM）>依那普利（LC50 = 2.0 mM）>卡托普利（LC50 = 20 mM）。用孕烯醇酮-16α-腈对大鼠进行体内预处理以诱导P450 3A亚家族的同工酶，可显著增强喹那普利、福辛普利和依那普利的细胞毒性，但不影响卡托普利的细胞毒性。用对其他同工酶亚家族具有选择性的P450诱导剂（乙醇、β-萘黄酮和苯巴比妥）进行预处理，并未改变任何一种ACEIs的体外毒性。与SKF525-A（15 microM）或醋竹桃霉素（0.1 mM）共同孵育可降低喹那普利、福辛普利和依那普利的肝毒性。用丁硫氨酸亚砜胺（2 mM）预孵育可增强喹那普利、福辛普利、依那普利和卡托普利的细胞毒性。本研究结果表明，与依那普利一样，喹那普利和福辛普利也可经历P450 3A依赖性生物活化，且解毒需要维持谷胱甘肽状态，而卡托普利引起的细胞毒性与细胞色素P450代谢无关。
